Thieno[3,2-c]pyridine derivatives, and particularly ticlopidine hydrochloride are known for their anti-inflammatory activity, vaso dilating activity, and blood platlet aggregation inhibitor activity, as described in U.S. Pat. No. 4,051,141 to Castaigne, the disclosure of which is incorporated herein by reference in its entirety.
Several methods are known for the synthesis of thieno[3,2-c]pyridine derivatives. For Example, U.S. Pat. No. 4,051,141 to Castaigne, proposed the synthesis of thieno-pyridine derivatives by condensation of a thieno[3,2-c]pyridine with o-chlorobenzyl chloride. U.S. Pat. No. 4,127,580 to Braye proposed another method of synthesizing thieno-pyridine derivatives. According to the method of Braye '580, ticlopidine could be prepared by reacting N-(2-chloro-benzyl)-2-(2- thienyl)ethylamine hydrochloride with formaldehyde to achieve the conversion to a free base, which could then be converted to the hydrochloride salt. U.S. Pat. No. 4,174,448 to Bousquet et al. proposes the reaction of N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine hydrochloride with a halogenomethyl ether, a halogenomethyl thio ether, a halogenomethyl ester, a S-hexahydro-S-triazine, a trioxane, dimethoxymethane, or a trithian to yield thieno-pyridine derivatives.
Still other proposed synthetic pathways utilize 2-(2-thienyl)ethylamine as the key intermediate to produce thieno-pyridine derivatives. For example, Japanese Patent No. 4-26690 proposes a method of preparing ticlopidine by reacting 2-(2-thienyl)ethylamine with 1,3-dioxolane.
U.S. Pat. No. 4,906,756 to Lodewijk et al. proposes the reaction of 2-(2-thienyl)ethylamine, prepared from 2-(2-nitrovinyl)thiophene, with formaldehyde to produce the formimine, cyclizing the formimine with hydrochloric acid to produce 4,5,6,7-tetrahydrothieno[3,2,c]pyridine, and converting this compound to ticlopidine free base by reaction with o-chlorobenzylchloride. The free base is then converted to ticlopidine hydrochloride.
U.S. Pat. No. 4,997,945 to Khatri proposes a method of making ticlopidine which involves reacting 2-(2'-thienyl)ethylamine, prepared from the carbamate salt thereof, with formaldehyde and proceeded as described in Lodewijk '756.
U.S. Pat. Nos. 5,068,360 and 5,191,090 both to DeHoff propose reacting an alkyl thienyl with gaseous or liquid ammonia respectively to produce 2-(2'-thienyl)ethylamine, and then producing ticlopidine by reaction of this intermediate with formaldehyde as described in Braye '580 and Lodewijk '756.
Accordingly, there remains a need in the art for additional methods of preparing thieno[3,2-c]pyridine derivatives such as ticlopidine hydrochloride. In addition, there remains a need in the art for methods of synthesizing thieno[3,2-c]pyridine derivatives which produce commercially viable yields of product in a relatively simple manner. Further, there remains a need in the art for a method of preparing thieno[3,2-c]pyridine derivatives which avoids the use of formaldehyde utilized in conventional manufacturing methods.
It is therefore an object of the present invention to provide a new method of preparing thieno[3,2-c]pyridine derivatives such as ticlopidine hydrochloride. It is further an object of the present invention to provide a method of preparing thieno[3,2-c]pyridine derivatives which avoids the use of formaldehyde.